Oxidative stress has been implicated in all stages of atherosclerosis, but how inherited variations in oxidative stress genes influence the severity of cardiovascular disease is not known. We tested associations between polymorphisms in candidate oxidative stress genes, plasma oxidative stress biomarkers, and cardiovascular mortality in an angiography cohort. Single nucleotide polymorphisms (SNPs) across 15 genes were selected by linkage disequilibrium tagging. Genotyping was performed using customized arrayed primer extension micro-arrays, with automated genotype calling methods. Effects of SNPs and haplotypes on plasma oxidative stress and coronary artery disease (CAD) were estimated using a stochastic estimation maximization algorithm. Proportionate hazards analyses were used to determine effects of single and combined genetic markers on cardiovascular mortality risk, and on the following oxidative stress biomarkers: myeloperoxidase (MPO), nitrotyrosine, oxidized low-density lipoprotein, and antioxidant capacity. Oxidative stress gene SNPs associated with CAD were combined into an oxidative stress risk allele score, which predicted disease presence (1.5-fold risk increase per allele, P < 0.001). Combined risk alleles were also associated with elevated plasma MPO (P < 0.003), an oxidative stress biomarker that predicts cardiovascular mortality. Genetic markers that represent lifetime oxidative stress burden may implicate specific oxidative stress pathways in the pathogenesis of atherosclerosis, and offer therapeutic opportunities.